1. Field of the Invention
The invention relates generally to derivatives of Itraconazole and more specifically to Itraconazole analogs and compositions as pharmaceuticals for the treatment of disease.
2. Background Information
Itraconazole is known for its use as a clinical agent for the treatment of a broad spectrum of fungal infections. However, it has been shown that Itraconazole also possesses potent in vitro and in vivo anti-angiogenic activity, and additionally inhibits both Hedgehog (Hh) signaling and the growth of murine medulloblastoma (MB) allografts with deregulated Hh activity. These observations have led to expansion of the potential therapeutic application of Itraconazole and have even sparked evaluation of this compound in four ongoing cancer clinical trials.
In an effort to better understand the structural parameters that influence anti-angiogenic activity, all eight stereoisomers of Itraconazole (1a-1h, FIG. 1) have been synthesized and the individual stereoisomers evaluated for in vitro anti-angiogenic and 14α-demethylase inhibition (14DM) dependent antifungal activities. The discrepancy between the activities in one pair of trans-stereoisomers 1e-1f and the other stereoisomers suggests that the molecular mechanism of Itraconazole in anti-angiogenesis is distinct from that for antifungal activity.
Although Itraconazole has demonstrated biological activity outside the realm of antifungal therapeutic regimens, little is known about the correlation between its pharmacological properties and structural features. The precise structural parameters of Itraconazole that are associated with its biological activity (e.g., Hh inhibitory activity) have not yet been ascertained. Thus, a need exists to elucidate the structure-activity relationship, for instance, in both anti-angiogenic and Hh targeting activity, and to exploit this knowledge in order to identify analogs of Itraconazole with greater potency and/or decreased side effects.